Disubstituted amino-alkyl benzhydryl amines



Patented Oct. 4, 1949 UNITED STATES Y DISUBSTITUTED AMINO-ALKYLBENZHYDRYL AMINES George Rieveschl, Jr.,

Mich., assignor to Parke, Davis Detroit, Mich., a corpo ration of GrossePointe Woods,

& Company Michigan No Drawing. Application April 8, 1946, Serial No.660,406

4 Claims. (Cl. 260570) This invention relates to certain organicdiamines and to This application methods for obtaining the same.

is a continuation-in-part of my copending application, Serial No.531,639, filed April 18, 1944 from which Patent No. 2,421,714

was issued June 3, 1947.

More particularly, this invention relates to w-N- aminoalkyl benzhydrylamines, the free bases of which have the formula where n is one of theintegers two and three, R1

and R2 are the same or diiferent substituents and represent hydrogen, analkyl radical containing 1 or 2 carbon atoms or an alkoxy radicalcontaining 1 or 2 carbon atoms, R3 and R4 are the same or diflerentalkyl radicals containing 1 to 3 carbon atoms inclusive or R3 and R4taken with N may be a saturated six-membered heterocyclic 'peridme, amethyl substituted piperidine, morpholine, morpholine, thiomorpholineand the like.

a methyl substituted The compounds of this invention may be obtained asthe free base having the they may be obtained in formula given above orthe form of their acid addition salts with organic and inorganic acids.

these salts are the hydrobromide, hydrochloride, phosphate, sulfate,

citrate, tartrate, salts.

I have found general formula by the reaction formula salicylate,benzoate and acetate that may of a compounds of the above be obtained inhigh yields benzhydryl halide of the with an aminoalkylamine of theformula Alternatively, a benzhydrylamine of the formula CHNH can bereacted formula with an aminoalkyl halide of the to obtain the newcompounds of the invention. In th above formulas 11., R1, R2, R3 and R4have the same significance as given above and X is a chlorine, bromineor iodine atom.

The processes for preparing these new compounds can be carried out inthe same manner. I have found that the reaction can be effected eitherare suitable for benzene, toluene,

terpentine, pyridine, di-n-butyl ether, xylene and the like. When thereaction is compounds.

Example l.' N-/i-diethylaminoethyl benzhydrylamine A mixture of g. offi-diethylaminoethylamine CHzCH:

subsided the mixture is heated on a steam bath for three hours. Themixture is cooled, treated with water and the resulting mixture madefrom the acid aqueous extracts by alkali and extracted with ether.

purified by refrom absolute ethanol;

98.8 g. of benzhydryl bromide and Example 2.-N-'y-diethylaminopropylbenzhydrylamine A mixture consisting of 264 g. of benzhydrylamine and 75g. of freshly distilled -diethylaminopropyl chloride is stirred andheated at 135 C. for eight hours. The reaction-mixture is cooled,treated with 1'75 cc. of N sodium hydroxide solution and extracted withether. ethe tract is dried, the ether distilled and the residuedistilled under reduced pressure, 0. a. 1 mm. of mercury, to obtain thefree base of the desired N-v-diethylaminopropyl benzhydrylamine as alight yellow oil. The free base can be converted to the dihydrochloridesalt by dissolving the base in ether and treating the solution with anexcess of dry hydrogen chloride. The white dihydrochloride salt whichseparates from the ether solution is collected and purified byrecrystallization from absolute ethanol. M. P. 141-145.

E :cample 3.-N 6-1 -piperidylethyl benzhydrylamine A mixture consistingof 124 g. of benzhydryl bromide and 128 g. of B-l-piperidylethylamine iswarmed on a steam bath for five hours, cooled and the reaction mixturetreated with 100 cc. of 5 N sodium hydroxide solution. The resultingmixture is extracted with ether, the ether extract dried and the etherdistilled. The residue is distilled under reduced pressure to obtain thedesired N-e-l-piperidylethyl benzhydrylamine.

The free base can be converted to the dihydrobromide salt by dissolvingthe base in absolute ethanol and adding an excess of alcoholic hydrogenbromide. The salt is precipitated from the solution by the addition ofether, collected and purified by recrystallization from absoluteethanol.

By using an equivalent amount of ,8-3-methyll-piperidyleth 'lamine inthe above procedure instead of the pl-piperidylethylamine, one obtainsN-p-S-methyl-l-piperidylethyl benzhydrylamine.

Example 4.'y-N-4-morpholinylpropyl benzhydrylamz'ne CHNH-CHzCHzUHzN O 0/mass.

A mixture consisting of 142 g. of 'y-l-morpholinylpropylarnine and 101g. of benzhydryl chloride in 300 cc. of dry pyridine is heated in aclosed vessel at 150 C. for six hours. After the reaction mixture hascooled, 100 g. of flake sodium hydroxide is added and the mixturestirred for twelve hours at room temperature. The sodium chloride-sodiumhydroxide is removed by filtration and the pyridine removed from thefiltrate by distillation. The residue is distilled underreduced'pressure, c. a. 1 mm. of mercury, to obtain the desired'y-N-4-morpholinylpropyl benzhydrylamine.

The citrate salt of -N-4-morpholinylpropyl Example5.-s-N-di-n-propylaminoethyl 4,4 -dz'methylbenzhydrylamine (Dir-O CHzCHzCH:

\ CHNHCH2CH2N CH3 CHBCHQCHK A mixture consisting of 136 g. of4,4-dimethylbenzhydryl bromide and 144 g. oi,B-di-n-propylaniinc-ethylamine is heated on a steam bath for six hours,cooled and treated with 200 cc. of 5 N sodium hydroxide solution. Themixture is extracted with ether, the ether extract dried and the etherdistilled. The residue which consists of a mixture of the desiredproduct and di-npropylaminoethylamine is heated under 1 mm. of mercuryat C. in order to remove the din-propylaminoethylamine. The residue,after cooling, is taken up in ether, the solution treated with an excessof dry hydrogen chloride gas and the crude clihydrochloride salt whichseparates collected. The pure white crystalline dihydrcchloride salt of,3-N-di-n-propylaminoethyl 4,4- dimethyl benzhydrylamine can be obtainedby recrystallization of the crude salt from absolute ethanol-ethermixture.

Example 6 .-fl-N -methylethylaminoeth.yl 2 -methoxybenzhydrylamine Amixture consisting of 138 g. of Z-rnethoxybenzhydryl bromide and 102 g.of fl-methylethylaminoethylamine is heated for four hours at C., cooledand the mixture treated with about 250 cc. of 5 N sodium hydroxidesolution. The mixture is extracted with ether, the ether extract washedwith water and then the ether solution extracted with several portionsof dilute hydrochloric acid. The free base of the desired product isliberated from the aqueous acid extracts by treatment with sodiumhydroxide solution and extracted with ether. The ether extract afterwashing with water and drying is treated with an excess of dry hydrogenbromide gas. The crude dihydrobrornide salt whichseparates is collectedand purified by recrystallization from absolute ethanol.

What I claim as my invention is:

l. A compound of the class consisting of a free base and its acidaddition salts, said free base hav ing the formula R 5:) 3 Hz GENE-(CH2)"N Ck Q CHzOH;

CHNH-CHzCHaN CHgCHg 3. A compound of the formula Q CHaCH:

GENE-CH2 CH2 4. A compound of the formula GEORGE RIEVESCHL, J H.

/CH: OHNH-OHQCHZN REFERENCES CITED The following references are ofrecord in the file of patent:

UNITED STATES PATENTS Name Date Martin Nov. 23, 1942 OTHER REFERENCESAlphen et a1., Red. Trav. Chim., v01. 54 (193! 0 pp. 361-365.

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